US2026034238A1PendingUtilityA1
Linkers, drug linkers and conjugates thereof and methods of using the same
Est. expiryJan 11, 2043(~16.5 yrs left)· nominal 20-yr term from priority
A61P 35/00A61K 47/68037A61K 47/68031A61K 47/6889A61K 47/6851A61K 47/6883
59
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Claims
Abstract
It provides linker compounds, or stereoisomers or salts thereof, including (a) a linker unit having from 1 to 4 attachment sites for a drug unit and having one of the following structures (i) or (ii): (b) at least one polar group containing a polymer unit, optionally a sugar unit, optionally a carboxyl unit, and combinations thereof; and (c) optionally a stretcher group having an attachment site for a targeting group, wherein a—is an attachment site to an enzyme-cleavable group; (3—is an attachment site to the at least one polar group; 6—is H, an attachment site to at least one of the drug unit, or an attachment site to a linking group attached to the at least one of the drug unit. It also provides drug-linker compounds and conjugates formed from linker compounds, as well as related pharmaceutical compositions and methods.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A Linker compound, or a stereoisomer or salt thereof, comprising:
(a) a Linker unit having from 1 to 4 attachment sites for a Drug unit and having one of the following structures (i) or (ii):
(b) at least one Polar group comprising a Polymer unit, optionally a Sugar unit, optionally a Carboxyl unit, and combinations thereof; and
(c) optionally a Stretcher group having an attachment site for a Targeting group;
wherein:
α— is an attachment site to an enzyme-cleavable group;
β—is an attachment site to the at least one Polar group;
δ—is H, an attachment site to at least one of the Drug units, or an attachment site to a linking group attached to the at least one of the Drug units;
the Polymer unit comprises a polyamide, a polyether, or a combination thereof, wherein the polyether comprises a hydroxyl group, a polyhydroxyl group, a sugar group, a carboxyl group, or combinations thereof;
each R a independently is H or C 1 -C 6 alkyl;
each R b independently is halo, C 1-6 alkyl, an attachment site to at least one of the Drug units, or an attachment site to at least one of the Polar groups;
x is 0, 1, 2, 3, or 4;
y is 0, 1, 2, or 3;
R c is a bond, —C(O)—, —S(O)—, —SO 2 —, C 1-6 alkylene, C 1-6 alkynylene, triazolyl, or combinations thereof; and
Y is a bond, —O—, —S—, —N(R a )—, —C(O)—, —S(O)—, —SO 2 —C 1 -C 6 alkylene, C 1 -C 6 alkenylene, C 1 -C 6 alkynylene, a group containing triazolyl, or combinations thereof.
2 . The Linker compound of claim 1 , wherein the Linker unit has one of the following structures (i-a), (ii-a), or (iii-a):
or a stereoisomer or salt thereof.
3 . The Linker compound of claim 1 , wherein the Linker unit has one of the following structures (i-b), (i-c), (i-d), (i-e), or (i-f):
or a stereoisomer or salt thereof.
4 . The Linker compound of claim 1 , wherein the Linker unit has the following structure (ii-b) or (iii-b):
or a stereoisomer or salt thereof.
5 . The Linker compound of any one of claims 1-4 , wherein the at least one Polar group comprises at least one Sugar unit having the following formula:
or a stereoisomer or salt thereof, wherein:
each X is independently selected from NH and O;
each R is independently selected from hydrogen, acetyl, a monosaccharide, a disaccharide, and a polysaccharide;
each X 1 is independently selected from CH 2 and C(O);
each X 2 is independently selected from H, OH and OR;
k is 1 to 10; and
L3 is a point of attachment to a remainder of the Polar group.
6 . The Linker compound any one of claims 1-4 , wherein the at least one Sugar unit has one of the following structures (XII) or (XIII):
or a stereoisomer or salt thereof, wherein:
each R is independently selected from hydrogen, a monosaccharide, a disaccharide and a polysaccharide;
m is 1 to 8; and
n is 0 to 4.
7 . The Linker compound of any one of claims 1-6 , comprising a Polar group having a formula selected from:
or a stereoisomer a salt thereof, wherein:
R 20 is an attachment group to site R b , or to the enzyme-cleavable group;
R 21 and R 22 are each, independently, a bond or C 1 -C 3 alkylene;
R 24 and R 25 are each independently selected from a H; polyhydroxyl group; substituted polyhydroxyl group; —C(O)-polyhydroxyl group; substituted —C(O)-polyhydroxyl group; substituted C 1 -C 8 alkyl; substituted —C(O)—C 1 -C 8 alkyl; a chelator; and —C(O)—R 28 , where R 28 is a Sugar unit of formula (XII) or (XIII), provided that R 24 and R 25 are not both H; and
n20 is 2 to 26; or
or a stereoisomer or salt thereof, wherein:
R 20 is an attachment group to site R b , or to the enzyme-cleavable group;
R 21 and R 22 are each, independently, a bond or C 1 -C 3 alkylene;
one of R 24 and R 25 is selected from a H; polyhydroxyl group; substituted polyhydroxyl group; —C(O)-polyhydroxyl group; substituted —C(O)-polyhydroxyl group; substituted C 1 -C 8 alkyl; substituted —C(O)—C 1 -C 8 alkyl; a chelator; and —C(O)—R 28 , where R 28 is a Sugar unit of formula (XII) or (XIII); and the other of R 24 and R 25 is a polyethylene glycol, optionally having 1 to 24 ethylene glycol subunits; and
n20 is 2 to 26; or
or a stereoisomer or salt thereof, wherein:
R 20 is an attachment group to site R b , or to the enzyme-cleavable group;
R 26 and R 27 are each optional and are, independently, selected from a bond, C 1 -C 12 alkylene, —NH—C 1 -C 12 alkylene, —C 1 -C 12 alkylene-NH—, —C 1 -C 12 alkylene-N(CH 3 )—, —C(O)—C 1 -C 12 alkylene, —C 1 -C 12 alkylene-C(O)—, —NH—C 1 -C 12 alkylene-C(O)— and —C(O)—C 1 -C 12 alkylene-NH—;
one of R 24 and R 25 is selected from a H; polyhydroxyl group; substituted polyhydroxyl group; —C(O)-polyhydroxyl group; substituted —C(O)-polyhydroxyl group; substituted C 1 -C 8 alkyl; substituted —C(O)—C 1 -C 8 alkyl; a chelator; and —C(O)—R 28 , where R 28 is a Sugar unit of formula (XII) or (XIII); and the other of R 24 and R 25 is selected from H; polyhydroxyl group; substituted polyhydroxyl group; —C(O)-polyhydroxyl group; substituted —C(O)-polyhydroxyl group, where R 28 is a Sugar unit of formula (XII) or (XIII); and polyethylene glycol, optionally having 1 to 24 ethylene glycol subunits, provided that R 24 and R 25 are not both H;
each R 29 is optional and independently selected from —C(O)—, —NH—, —C(O)—C 1 -C 6 alkylene-, —NH—C 1 -C 6 alkylene-, —C 1 -C 6 alkylene-NH—, —C 1 -C 6 alkylene-C(O)—, —NH(CO)—C 1 -C 6 alkylene-, —N(CH 3 )—(CO)—C 1 -C 6 alkylene-, —NH(CO)NH—, and triazole;
n20 is 2 to 26;
n21 is 1 to 4; and
n27 is 1 to 4, or
or a stereoisomer or salt thereof, wherein:
R 20 is an attachment group to site R b , or to the enzyme-cleavable group;
R 21 is a bond or C 1 -C 3 alkylene,
—C 1 -C 3 alkylene-[O—CH 2 —CH 2 -] n20 , —[CH 2 —CH 2 —O] n20 —C 1 -C 3 alkylene- or —C 1 -C 3 alkylene-[O—CH 2 —CH 2 -] n20 -C(O)—;
R 22 is C 1 -C 3 alkylene, —C 1 -C 3 alkylene-[O—CH 2 —CH 2 -] n20 , —[CH 2 —CH 2 —O] n20 —C 1 -C 3 alkylene- or —C 1 -C 3 alkylene-[O—CH 2 —CH 2 -] n20 -C(O)—;
each R α is independently H or —R 22 —NR 24 R 25 ;
each R N is independently H, C 1 -C 6 alkyl or —R 22 —NR 24 R 25 ;
R 24 and R 25 are each independently selected from a H; polyhydroxyl group; substituted polyhydroxyl group; —C(O)-polyhydroxyl group; substituted —C(O)-polyhydroxyl group; substituted C 1 -C 8 alkyl; substituted —C(O)—C 1 -C 8 alkyl; a chelator; and —C(O)—R 28 , where R 28 is a Sugar unit of formula (XII) or (XIII), provided that R 24 and R 25 are not both H; and
each n20 is independently 2 to 26, or
or a stereoisomer or salt thereof, wherein:
R 20 is an attachment group to site R b , or to the enzyme-cleavable group;
R 21 and R 22 are each, independently, a bond, C 1 -C 3 alkylene, or —C 1 -C 3 alkylene[O—CH 2 —CH 2 -] n20 ;
each R α is independently H or —R 22 —NR 24 R 25 ;
each R N is independently H, C 1 -C 6 alkyl or —R 22 —NR 24 R 25 ;
R 24 and R 25 are each independently selected from a H; polyhydroxyl group; substituted polyhydroxyl group; —C(O)-polyhydroxyl group; substituted —C(O)-polyhydroxyl group; substituted C 1 -C 8 alkyl; substituted —C(O)—C 1 -C 8 alkyl; a chelator; and —C(O)—R 28 , where R 28 is a Sugar unit of formula (XII) or (XIII), provided that R 24 and R 25 are not both H;
R 26 is H or C 1 -C 4 alkyl; and
each n20 is independently 2 to 26,
with the proviso that at least one R a or R N is —R 22 —NR 24 R 25 ; or
or a stereoisomer or salt thereof, wherein:
R 20 is an attachment group to site R b , or to the enzyme-cleavable group;
R 21 and R 22 are each, independently, a bond, C 1 -C 3 alkylene, or —C 1 -C 3 alkylene-[O—CH 2 —CH 2 -] n20 ;
each R α is independently H or —R 22 —NR 24 R 25 ;
each R N is independently H or C 1 -C 6 alkyl;
each R 23 is independently C 1 -C 6 alkylene;
R 24 and R 25 are each independently selected from a H; polyhydroxyl group; substituted polyhydroxyl group; —C(O)-polyhydroxyl group; substituted —C(O)-polyhydroxyl group; substituted C 1 -C 8 alkyl; substituted —C(O)—C 1 -C 8 alkyl; a chelator; and —C(O)—R 28 , where R 28 is a Sugar unit of formula (XII) or (XIII), provided that R 24 and R 25 are not both H; and
each n20 is independently 2 to 26.
8 . The Linker compound of claim 7 , wherein R 24 and R 25 are each independently selected from H and a polyhydroxyl group, provided that R 24 and R 25 are not both H.
9 . The Linker compound of claim 7 or 8 , wherein the polyhydroxyl group is a linear monosaccharide, optionally selected from a C6 or C5 sugar, a sugar acid, and an amino sugar.
10 . The Linker compound of claim 9 , wherein:
the C6 or C5 sugar is selected from glucose, ribose, galactose, mannose, arabinose, 2-deoxyglucose, glyceraldehyde, erythrose, threose, xylose, lyxose, allose, altrose, gulose, idose, talose, aldose, and ketose; the sugar acid is selected from gluconic acid, aldonic acid, uronic acid, and ulosonic acid; or the amino sugar is selected from glucosamine, N-acetyl glucosamine, galactosamine, and N-acetyl galactosamine.
11 . The Linker compound of any one of claims 7 to 10 , comprising a Polar group selected from the following, or a stereoisomer or salt thereof:
wherein each R is independently H or alkyl; each R 39 is independently selected from H, a linear monosaccharide and polyethylene glycol, optionally having from 1 to 24 ethylene glycol subunits; each n independently is 1-12; and the wavy line is an attachment site to R b , or to the enzyme-cleavable group.
12 . The Linker compound of claim 7 or 8 , wherein one of R 24 and R 25 is a linear monosaccharide and the other is a cyclic monosaccharide.
13 . The Linker compound of claim 12 , comprising a Polar group selected from the following, or a stereoisomer or salt thereof:
wherein R 41 is a cyclic monosaccharide; and the wavy line is an attachment site to R b , or to the enzyme-cleavable group.
14 . The Linker compound of claim 7 , wherein R 24 and R 25 are independently a polyhydroxyl selected from a cyclic monosaccharide, disaccharide, and polysaccharide.
15 . The Linker compound of claim 14 , comprising a Polar group selected from the following, or a stereoisomer or salt thereof:
wherein each R 45 is selected from H and a monosaccharide, a disaccharide, or a polysaccharide; and R 46 is selected from a cyclic monosaccharide, disaccharide, or polysaccharide; and the wavy line is an attachment site to R b , or to the enzyme-cleavable group.
16 . The Linker compound of claim 7 , wherein R 24 and R 25 are independently selected from a linear monosaccharide and a substituted linear monosaccharide, wherein the substituted linear monosaccharide is substituted with a monosaccharide, a disaccharide, or a polysaccharide.
17 . The Linker compound of claim 16 , comprising a Polar group selected from the following, or a stereoisomer or salt thereof:
wherein R 47 is a linear monosaccharide; and each R 49 is selected from a monosaccharide, a disaccharide, and a polysaccharide; and the wavy line is an attachment site to R b , or to the enzyme-cleavable group.
18 . The Linker compound of claim 7 , wherein R 24 and R 25 are independently selected from a linear monosaccharide and a substituted monosaccharide, wherein the substituted linear monosaccharide is substituted with one or more substituents selected from carboxyl, ester, and amide, and optionally further substituted with a monosaccharide, disaccharide, or a polysaccharide.
19 . The Linker compound of claim 18 , comprising a Polar group selected from the following, or a stereoisomer or salt thereof:
wherein each R 42 is independently selected from a linear monosaccharide and a substituted linear monosaccharide; each R 43 is independently selected from hydroxyl, carboxyl, ester, and amide; and the wavy line is an attachment site to R b , or to the enzyme-cleavable group.
20 . The Linker compound of claim 7 , wherein one of R 24 and R 25 is a —C(O)-polyhydroxyl group or substituted —C(O)-polyhydroxyl group, and the other of R 24 and R 25 is a H, —C(O)-polyhydroxyl group, substituted —C(O)-polyhydroxyl group, polyhydroxyl group or substituted polyhydroxyl group; wherein the substituted —C(O)-polyhydroxyl group and polyhydroxyl group are substituted with a monosaccharide, a disaccharide, a polysaccharide, carboxyl, ester, or amide.
21 . The Linker compound of claim 18 or 20 , comprising a Polar group selected from the following, or a stereoisomer or salt thereof:
wherein the wavy line is an attachment site to R b , or to the enzyme-cleavable group.
22 . The Linker compound of claim 7 , wherein R 24 and R 25 are independently H or substituted —C 1 -C 8 alkyl, provided that both R 24 and R 25 are not H; wherein substituted —C 1 -C 8 alkyl is substituted with hydroxyl and/or carboxyl.
23 . The Linker compound of claim 22 , comprising a Polar group selected from the following, or a stereoisomer or salt thereof:
wherein R 48 is selected from H, OH, CH 2 OH, COOH, or —C 1 -C 6 alkyl substituted with hydroxyl or carboxyl; and the wavy line is an attachment site to R b , or to the enzyme-cleavable group.
24 . The Linker compound of claim 7 , wherein one of R 24 and R 25 is H or substituted —C(O)—C 1 -C 8 alkyl, and the other of R 24 and R 25 is substituted —C(O)—C 1 -C 8 alkyl, or substituted —C 1 -C 8 alkyl, wherein substituted —C(O)—C 1 -C 8 alkyl and substituted —C 1 -C 8 alkyl, are substituted with hydroxyl and/or carboxyl.
25 . The Linker compound of claim 24 , comprising a Polar group selected from the following, or a stereoisomer or salt thereof:
wherein the wavy line is an attachment site to R b , or to the enzyme-cleavable group.
26 . The Linker compound of claim 7 , wherein R 24 and R 25 are independently selected from H and a chelator, wherein the chelator is optionally attached to the nitrogen of —NR 24 R 25 by an alkylene, arylene, carbocyclo, heteroarylene, or heterocarbocylo; provided that both R 24 and R 25 are not H.
27 . The Linker compound of claim 26 , wherein the chelator is selected from ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), triethylenetetraminehexaacetic acid (TTHA), benzyl-DTPA, 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (DOTA), benzyl-DOTA, 1,4,7-triazacyclononane-N,N′,N″-triacetic acid (NOTA), benzyl-NOTA, 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA) and N,N′-dialkyl substituted piperazine.
28 . The Linker compound of claim 27 , comprising a Polar group selected from the following, or a stereoisomer or salt thereof:
wherein the wavy line is an attachment site to R b , or to the enzyme-cleavable group.
29 . The Linker compound of any one of claims 6 to 20 , wherein each monosaccharide is independently selected from:
a C5 or C6 sugar selected from glucose, ribose, galactose, mannose, arabinose, 2-deoxyglucose, glyceraldehyde, erythrose, threose, xylose, lyxose, allose, altrose, gulose, idose talose, aldose, and ketose; a sugar acid selected from gluconic acid, aldonic acid, uronic acid and ulosonic acid; or an amino sugar selected from glucosamine, N-acetyl glucosamine, galactosamine, and N-acetyl galactosamine.
30 . The Linker compound of any one of claims 1 to 29 , wherein the attachment site is formed from a functional group of a precursor compound of the Polar group, said functional group selected from halo, aldehyde, carboxyl, amino, alkynyl, azido, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acyl sulfonamide, alkyl sulfonate, triazole, azadibenzocyclooctyne, hydrazine, carbonylalkylheteroaryl, and protected forms thereof.
31 . The Linker compound of any one of claims 1 to 6 , comprising a Polar group having a formula selected from the following:
or a stereoisomer or salt thereof, wherein:
R 20 is an attachment group to site R b , or to the enzyme-cleavable group;
R 21 and R 22 are each independently, a bond or C 1 -C 3 alkylene groups;
R 30 is selected from an optionally substituted C 3 -C 10 carbocycle; thiourea; optionally substituted thiourea; urea; optionally substituted urea; sulfamide; alkyl sulfamide; acyl sulfamide, optionally substituted alkyl sulfamide; optionally substituted acyl sulfamide; sulfonamide; optionally substituted sulfonamide; guanidine, including alkyl and aryl guanidine; phosphoramide; or optionally substituted phosphoramide; or R 30 is selected from azido, alkynyl, substituted alkynyl, —NH—C(O)-alkynyl, —NH—C(O)— alkynyl-R 65 ; cyclooctyne; —NH-cyclooctyne, —NH—C(O)-cyclooctyne, or —NH-(cyclooctyne) 2 ; wherein R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle or optionally substituted heteroaryl; and
n20 is 2 to 26;
or a stereoisomer or salt thereof, wherein:
R 20 is an attachment group to site R b , or to the enzyme-cleavable group;
R 21 and R 22 are each, independently, a bond or C 1 -C 3 alkylene groups;
R 31 is a branched polyethylene glycol chain, each branch having 1 to 26 ethylene glycol subunits and each branch having an R 35 at its terminus;
R 35 is azido, alkynyl, alkynyl-R 65 , cyclooctyne or cyclooctyne-R 65 , wherein R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle or optionally substituted heteroaryl; and
n20 is 2 to 26;
or a stereoisomer or salt thereof, wherein:
R 20 is an attachment group to site R b , or to the enzyme-cleavable group;
R 21 and R 22 are each, independently, a bond or C 1 -C 3 alkylene groups;
R 31 is a branched polyethylene glycol chain, each branch, independently, having 1 to 26 ethylene glycol subunits and each branch having an R 35 at its terminus;
R 35 is azido, alkynyl, alkynyl-R 65 , cyclooctyne or cyclooctyne-R 65 , wherein R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle and optionally substituted heteroaryl; and
n20 is 2 to 26;
or a stereoisomer or salt thereof, wherein:
R 20 is an attachment group to site R b , or to the enzyme-cleavable group;
R 31 is H or R 22 —NR 24 R 25 ; R 21 and R 22 are each, independently, a bond or C 1 -C 3 alkylene groups;
R 24 and R 25 are each independently selected from a H; polyhydroxyl group; substituted polyhydroxyl group; —C(O)-polyhydroxyl group; substituted —C(O)-polyhydroxyl group, provided that R 24 and R 25 are not both H; and
n20 is 2 to 26;
or a stereoisomer or salt thereof, wherein:
R 20 is an attachment group to site R b , or to the enzyme-cleavable group;
R 21 and R 22 are each, independently, a bond or C 1 -C 3 alkylene groups;
R 31 is a branched polyethylene glycol chain, each branch having 1 to 26 ethylene glycol subunits and each branch having an R 35 at its terminus;
R 33 is C 1 -C 3 alkylene, C 1 -C 3 alkylene-C(O), —C(O)—C 1 -C 3 alkylene, or —C(O)—C 1 -C 3 alkylene-C(O);
R 35 is azido, alkynyl, alkynyl-R 65 , cyclooctyne or cyclooctyne-R 65 , wherein R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle or optionally substituted heteroaryl; and
n20 is 2 to 26;
or a stereoisomer or salt thereof, wherein:
R 20 is an attachment group to site R b , or to the enzyme-cleavable group;
each R 21 is independently a bond, —O— or C 1 -C 3 alkylene group;
each R 34 is independently H, —[CH 2 —CH(OH)—CH 2 —O] n20 —R 36 , —C(O)—NR 24 R 25 or —C(O)N(R N )—C 1 -C 6 alkylene-NR 24 R 25 ;
R N is H or C 1 -C 4 alkyl;
R 24 and R 25 are each independently selected from a H; polyhydroxyl group; or
substituted polyhydroxyl group, provided that both R 24 and R 25 are not H;
each R 36 is independently H, C 1 -C 6 alkylene-C(OH)H—NR 44 R 45 , C 1 -C 6 alkylene-C(OH)H—C 1 -C 6 alkylene-NR 44 R 45 , —C(O)—NR 24 R 25 , —C(O)N(R N )—C 1 -C 6 alkylene-NR 24 R 25 , C 1 -C 6 alkylene-C(O)NR 24 R 25 or C 1 -C 6 alkylene-CO 2 R 37 ;
each R 37 is independently H or C 1 -C 6 alkyl;
R 44 and R 45 are each independently selected from a H; polyhydroxyl group; substituted polyhydroxyl group; —C(O)-polyhydroxyl group; and substituted —C(O)-polyhydroxyl group, provided that both R 44 and R 45 are not H;
each n20 is independently 1 to 26; and
n25 is 1 or 2;
or a stereoisomer or salt thereof, wherein:
R 20 is an attachment group to site R b , or to the enzyme-cleavable group;
R 21 , R 22 and R 23 are each independently a bond or C 1 -C 3 alkylene group;
R 24 and R 25 are each independently selected from a H; polyhydroxyl group; substituted polyhydroxyl group; —C(O)-polyhydroxyl group; and substituted —C(O)-polyhydroxyl group, provided that R 24 and R 25 are not both H;
each n20 is independently 0 to 26, and each n21 is independently 0 to 26, with the proviso that at least one of n20 or n21 is 2 to 26;
n22 is 1 to 5;
each n23 is independently 1 or 2;
or a stereoisomer or salt thereof, wherein:
R 20 is an attachment group to site R b , or to the enzyme-cleavable group;
R 21 and R 22 are each independently a bond or C 1 -C 3 alkylene groups;
R N is H or C 1 -C 4 alkyl;
R 24 and R 25 are each independently selected from a H; polyhydroxyl group; and
substituted polyhydroxyl group, provided that both R 24 and R 25 are not H;
each R 34 is independently H, —[CH 2 —CH(OH)—CH 2 —O] n20 —R 36 or —C(O)N(R N )—C 1 -C 6 alkylene-NR 24 R 25 ;
each R 36 is independently H, C 1 -C 6 alkylene-C(OH)H—NR 44 R 45 , C 1 -C 6 alkylene-C(OH)H—C 1 -C 6 alkylene-NR 44 R 45 , —C(O)N(R N )—C 1 -C 6 alkylene-NR 24 R 25 , C 1 -C 6 alkylene-C(O)NR 24 R 25 or C 1 -C 6 alkylene-CO 2 R 37 ;
each R 37 is independently H or C 1 -C 6 alkyl;
R 44 and R 45 are each independently selected from a H; polyhydroxyl group; substituted polyhydroxyl group; —C(O)-polyhydroxyl group; and substituted —C(O)-polyhydroxyl group; provided that both R 44 and R 45 are not H;
n20 is 2 to 26;
n21 is 1 to 26; and
n25 is 1 or 2;
or a stereoisomer or salt thereof, wherein:
R 20 is an attachment group to site R b , or to the enzyme-cleavable group;
R 21 and R 22 are each independently a bond or C 1 -C 3 alkylene groups;
R N is H or C 1 -C 4 alkyl;
R 24 and R 25 are each independently selected from a H; polyhydroxyl group; and substituted polyhydroxyl group, provided that R 24 and R 25 are not both H;
n20 is 2 to 26;
n21 is 1 to 4; and
n25 is 1, 2 or 3;
or a stereoisomer or salt thereof, wherein:
R 20 is an attachment group to site R b , or to the enzyme-cleavable group;
R 21 and R 22 are each, independently, a bond, C 1 -C 3 alkylene, —C 1 -C 3 alkylene-[O—CH 2 —CH 2 -] n20 , —[CH 2 —CH 2 —O] n20 —C 1 -C 3 alkylene- or —C 1 -C 3 alkylene-[O—CH 2 —CH 2 -] n20 -C(O)—;
each R α is independently H or —R 22 —NR 24 R 25 ;
each R N is independently H, C 1 -C 6 alkyl or —R 22 —NR 24 R 25 ;
R 24 and R 25 are each independently selected from a H; polyhydroxyl group; substituted polyhydroxyl group; —C(O)-polyhydroxyl group; substituted —C(O)-polyhydroxyl group;
substituted —C(O)—C 1 -C 8 alkyl; a chelator; —C(O)—R 28 , wherein R 28 is a Sugar unit of formula (XII) or (XIII), provided that R 24 and R 25 are not both H;
each n20 is independently 0 to 26, with the proviso that at least one n20 is 2 to 26; and
n25 is 1 or 2; or
or a stereoisomer or salt thereof, wherein:
R 20 is an attachment group to site R b , or to the enzyme-cleavable group;
R 21 , R 22 and R 23 are each, independently, a bond, C 1 -C 3 alkylene, —C 1 -C 3 alkylene-[O—CH 2 —CH 2 -] n20 , —[CH 2 —CH 2 —O] n20 —C 1 -C 3 alkylene- or —C 1 -C 3 alkylene-[O—CH 2 —CH 2 -] n20 -C(O)—;
each R α is independently H or —R 22 —NR 24 R 25 ;
each R N is independently H, C 1 -C 6 alkyl or —R 22 —NR 24 R 25 ;
R 24 and R 25 are each independently selected from a H; polyhydroxyl group; substituted polyhydroxyl group; —C(O)-polyhydroxyl group; substituted —C(O)-polyhydroxyl group;
substituted —C(O)—C 1 -C 8 alkyl; a chelator; and —C(O)—R 28 , where R 28 is a Sugar unit of formula (XII) or (XIII), provided that R 24 and R 25 are not both H;
R 26 is H or C 1 -C 6 alkyl;
each n20 is independently 0 to 26, with the proviso that at least one n20 is 2 to 26; and
each n21 is independently 0 to 26, with the proviso that at least one n21 is 2 to 26.
32 . The Linker compound of any one of claims 1 to 6 , comprising a Polar group having a formula selected from the following, or a stereoisomer or salt thereof:
wherein:
R 20 is an attachment group to site R b , or to the enzyme-cleavable group;
R 21 and R 22 are each, independently, a bond or C 1 -C 3 alkylene groups;
R 31 is a branched polyethylene glycol chain, each branch having 1 to 26 ethylene glycol subunits and each branch having an R 35 at its terminus;
R 33 is C 1 -C 3 alkylene, —C 1 -C 3 alkylene-C(O), —C(O)—C 1 -C 3 alkylene or —C(O)—C 1 -C 3 alkylene-C(O);
R 35 is azido, alkynyl, alkynyl-R 65 , cyclooctyne or cyclooctyne-R 65 , wherein R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle or optionally substituted heteroaryl; the wavy (˜) line indicates an attachment site to R 20 ; and n20 is 2 to 26.
33 . The Linker compound of claim 31 or 32 , comprising a Polar group formed from a precursor group selected from the following:
wherein R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle or optionally substituted heteroaryl; and the wavy line is an attachment site to R b , or to the enzyme-cleavable group.
34 . The Linker compound of any one of claims 31 to 33 , wherein the attachment site to R b , or to the enzyme-cleavable group is formed from a functional group of a precursor compound of the Polar group, said functional group selected from halo, aldehyde, carboxyl, amino, alkynyl, azido, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acyl sulfonamide, alkyl sulfonate, triazole, azadibenzocyclooctyne, hydrazine, carbonylalkylheteroaryl, and protected forms thereof.
35 . The Linker compound of any one of claims 1-6 , comprising a Polar group having a formula:
˜R 20 —(R 43 —R 41 —[O—CH 2 —CH 2 ] n40 —R 42 —R 43 —(NR 44 R 45 ) n41 )n 42 (XL)
or a stereoisomer or salt thereof, wherein: R 20 is an attachment group to site R b , or to the enzyme-cleavable group; R 41 and R 42 are each, independently, a bond or C 1 -C 6 alkylene; each R 43 is, independently, selected from a bond, C 1 -C 12 alkylene, —OC 1 -C 12 alkylene, —C(═O)—, —NR a —C 1 -C 12 alkylene, —C 1 -C 12 alkylene-NR a —, —C(O)—C 1 -C 12 alkylene, —C 1 -C 12 alkylene-C(O)—, —NR a —C 1 -C 12 alkylene-C(O)—, —C(O)—C 1 -C 12 alkylene-NR a —, —NR a —C(O)—NR a —, —NR a —C(O)—, —NR a —C(O)—C 1 -C 12 alkylene, —C(O)—NR a —C 1 -C 12 alkylene, -heteroarylene, heteroaryl-C 1 -C 12 alkylene, heteroaryl-C 1 -C 12 alkylene-C(O)—, or —C(O)NR 46 R 47 , wherein each alkylene is optionally substituted with hydroxyl, SO 3 H and/or oxo, R a is H, C 1 -C 6 alkyl, a polyhydroxyl group, or a substituted polyhydroxyl group, and one of R 46 and R 47 is H or C 1 -C 12 alkylene and the other is C 1 -C 12 alkylene, wherein one of the C 1 -C 2 alkylenes is bound to NR 44 R 45 at the nitrogen atom; R 44 and R 45 are each, independently, H, polyhydroxyl group, substituted polyhydroxyl group, —C(O)-polyhydroxyl group, or substituted —C(O)-polyhydroxyl group, wherein optional substituents are selected from sulfate, phosphate, alkyl sulfate, and alkyl phosphate; n40 is 2 to 26, provided that R 44 and R 45 are not both H; n40 is 2 to 26; n41 is 1 to 6; and n42 is 1 to 6.
36 . The Linker compound of any one of claims 1-6 , comprising a Polar group having a formula:
or a stereoisomer or salt thereof, wherein:
R 20 is an attachment group to site R b , or to the enzyme-cleavable group;
R 41 and R 42 are each, independently, a bond or C 1 -C 6 alkylene;
R 43 is selected from a bond, C 1 -C 12 alkylene, —OC 1 -C 12 alkylene, —C(═O)—, —NR a —C 1 -C 12 alkylene, —C 1 -C 12 alkylene-NR a —, —C(O)—C 1 -C 12 alkylene, —C 1 -C 12 alkylene-C(O)—, —NR a —C 1 -C 12 alkylene-C(O)—, —C(O)—C 1 -C 12 alkylene-NR a —, —NR a —C(O)—NR a —, —NR a —C(O)—, —NR a —C(O)—C 1 -C 12 alkylene, C(O)—NR a —C 1 -C 12 alkylene, -heteroarylene, heteroaryl-C 1 -C 12 alkylene, heteroaryl-C 1 -C 12 alkylene-C(O)—, and —C(O)NR 46 R 47 , wherein each alkylene is optionally substituted with hydroxyl, SO 3 H and/or oxo, R a is H, C 1 -C 6 alkyl, a polyhydroxyl group, or a substituted polyhydroxyl group and one of R 46 and R 47 is H or C 1 -C 12 alkylene and the other is C 1 -C 12 alkylene, wherein one of the C 1 -C 2 alkylenes is bound to NR 44 R 45 at the nitrogen atom;
R 44 and R 45 are each, independently, H, polyhydroxyl group, substituted polyhydroxyl group, —C(O)-polyhydroxyl group, or substituted —C(O)-polyhydroxyl group, wherein optional substituents are selected from sulfate, phosphate, alkyl sulfate, and alkyl phosphate, provided that R 44 and R 45 are not both H;
n40 is 1 to 26;
n41 is 1 to 6; and
n42 is 1 to 6.
37 . The Linker compound of any one of claims 1-6 , comprising a Polar group having a formula:
or a stereoisomer or salt thereof, wherein:
R 20 is an attachment group to site R b , or to the enzyme-cleavable group;
R 41 and R 42 are each, independently, a bond or C 1 -C 3 alkylene;
R 43 is selected from a bond, C 1 -C 6 alkylene, —OC 1 -C 12 alkylene, —C(═O)—, —NR a —C 1 -C 12 alkylene, —C 1 -C 6 alkylene-NR a —, —C(O)—C 1 -C 6 alkylene, -C 1 -C 8 alkylene-C(O)—, —NR a —C 1 -C 6 alkylene-C(O)—, —C(O)—C 1 -C 6 alkylene-NR a —, —NR a —C(O)—NR a —, —NR a —C(O)—, —NR a —C(O)—C 1 -C 8 alkylene, —C(O)—NR a —C 1 -C 12 alkylene, -heteroarylene, heteroaryl-C 1 -C 6 alkylene, heteroaryl-C 1 -C 6 alkylene-C(O)—, and —C(O)NR 46 R 47 , wherein each alkylene is optionally substituted with hydroxyl, SO 3 H, and/or oxo, R a is H, C 1 -C 6 alkyl, a polyhydroxyl group, or a substituted polyhydroxyl group and one of R 46 and R 47 is H or C 1 -C 6 alkylene and the other is C 1 -C 12 alkylene, wherein one of the C 1 -C 2 alkylenes is bound to NR 44 R 45 at the nitrogen atom;
R 44 and R 45 are each, independently, H, polyhydroxyl group, substituted polyhydroxyl group, —C(O)-polyhydroxyl group, or substituted —C(O)-polyhydroxyl group, wherein optional substituents are selected from sulfate, phosphate, alkyl sulfate, and alkyl phosphate, provided that R 44 and R 45 are not both H;
n40 is 1 to 16;
n41 is 1 to 4; and
n42 is 1 to 4.
38 . The Linker compound of any one of claims 7, 31, 32, and 35-37 , wherein R 20 is formed from a functional group of a precursor compound of the Polar group, said functional group selected from halo, aldehyde, carboxyl, amino, alkynyl, azido, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acyl sulfonamide, alkyl sulfonate, triazole, azadibenzocyclooctyne, hydrazine, carbonylalkylheteroaryl, or protected forms thereof.
39 . The Linker compound of any one of claims 7, 31, 32, and 35-37 , wherein R 20 comprises one of the following structures:
or a stereoisomer thereof, wherein R is H, C 1 -C 6 alkyl or polyhydroxyl group, n is 0 to 12, the ( , *) indicates an attachment site to R b , or to the enzyme-cleavable group, and the ( ) indicates an attachment site to a remainder portion of the Polar group.
40 . The compound of any one of claims 7, 31, 32, and 35-37 , wherein R 20 has one of the following structures:
or a stereoisomer thereof, wherein n=0 to 12, the ( *) indicates an attachment site to R b , or to the enzyme-cleavable group, and the ( ) indicates an attachment site to a remainder portion of the Polar group.
41 . The Linker compound of any one of claims 35-40 , wherein R 43 —(NR 44 R 45 ) n41 has one of the following structures:
or a stereoisomer thereof, wherein R a is H, C 1 -C 8 alkyl, a polyhydroxyl group, or a substituted polyhydroxyl group; p is an integer from 1 to 6, and the ( ) indicates the attachment site of R 43 to the remainder of the Polar group.
42 . The Linker compound of anyone of claims 35-40 , wherein R 43 —(NR 44 R 45 ) n41 has one of the following structures:
or a stereoisomer thereof, wherein the ( ) indicates the attachment site of R 43 to the remainder of the Polar group.
43 . The Linker compound of any one of claims 35-42 , wherein —NR 44 R 45 has one of the following structures:
or a stereoisomer thereof, wherein the ( ) indicates the attachment site of —NR 44 R 45 to the remainder of the Polar group.
44 . The Linker compound of any one of claims 1 - 44 , comprising a Polar group having one of the following structures prior to attachment to the Linker Unit:
wherein:
(*) indicates the attachment site to site R b , or to the enzyme-cleavable group;
each R is independently H or C 1 -C 6 alkyl;
R′ is H, C 1 -C 6 alkyl, —N(R 24 )(R 25 ) or —CO 2 H;
each n is independently 1 to 12;
X is 0, NR or —CH 2 —;
V is bond or C 1 -C 6 alkyl;
one of R 24 and R 25 is selected from a H; polyhydroxyl group; substituted polyhydroxyl group; —C(O)-polyhydroxyl group; substituted —C(O)-polyhydroxyl group; substituted —C(O)—C 1 -C 8 alkyl; a chelator; and —C(O)—R 28 , where R 28 is a Sugar unit of formula (XII) or (XIII); and the other of R 24 and R 25 is selected from H; polyhydroxyl group; substituted polyhydroxyl group; —C(O)-polyhydroxyl group; substituted —C(O)-polyhydroxyl group; substituted —C(O)—C 1 -C 8 alkyl; a chelator; —C(O)—R 28 , where R 28 is a Sugar unit of formula (XII) or (XIII); and polyethylene glycol, optionally having 1 to 24 ethylene glycol subunits, provided that R 24 and R 25 are not both H.
45 . The Linker compound of any one of claims 1-6 , comprising a Polar group having a formula selected from:
or a stereoisomer or salt thereof, wherein:
R 40 is an attachment group to site R b , or to the enzyme-cleavable group;
R 41 and R 42 are each, independently, a bond or C 1 -C 6 alkylene;
each R 43 is, independently, selected from a bond, C 1 -C 12 alkylene, —OC 1 -C 12 alkylene, —C(═O)—, —NH—C 1 -C 12 alkylene, —C 1 -C 12 alkylene-NH—, —C(O)—C 1 -C 12 alkylene, —C 1 -C 12 alkylene-C(O)—, —NH—C 1 -C 12 alkylene-C(O)—, —C(O)—C 1 -C 12 alkylene-NH—, —NH—C(O)—NH—, —NH—C(O)—, —NH—C(O)—C 1 -C 12 alkylene, —C(O)—NH—C 1 -C 12 alkylene, C 1 -C 12 alkylene-NH—C(O)—, -heteroarylene, heteroaryl-C 1 -C 12 alkylene, heteroaryl-C 1 -C 12 alkylene-C(O)—, or —C(O)NR 46 R 47 , wherein one of R 46 and R 47 is H or C 1 -C 12 alkylene and the other is C 1 -C 12 alkylene;
R 44 and R 45 are each, independently, H, polyhydroxyl group, substituted polyhydroxyl group, —C(O)-polyhydroxyl group, or substituted —C(O)-polyhydroxyl group, wherein optional substituents are selected from sulfate, phosphate, alkyl sulfate, and alkyl phosphate, provided that R 44 and R 45 are not both H;
each R 46 is independently selected from —NR 50 —, —NR 50 —C 1 -C 6 alkylene-NR 50 —, —NR 50 —C(O)—NR 50 —S(O) 2 —NR 50 — or —NR 50 —C(O)—C 1-6 alkylene-;
each R 50 is independently selected from H, C 1 -C 6 alkyl, or polyhydroxyl group;
each n40 is independently 2 to 26;
n41 is 1 to 6; and
n42 is 1 to 6;
or a stereoisomer or salt thereof, wherein:
R 40 is an attachment group to site R b , or to the enzyme-cleavable group;
R 51 , R 52 , R 53 and R 54 are each, independently, a bond or C 1 -C 6 alkylene;
X 1 , X 2 and X 3 are each independently —NR N —C(O)— or —C(O)—NR N —;
each R N independently represent H, C 1 -C 6 alkyl, or polyhydroxyl group;
R 55 and R 56 each independently represent a bivalent polyhydroxyl group;
R 57 is H, OH or C 1 -C 6 alkyl;
each n43 is independently 0 to 26, with the proviso that at least one n43 is 1 to 26;
n44 is 0 to 10; and
n45 is 1 or 2; or
or a stereoisomer or salt thereof, wherein:
R 40 is an attachment group to site R b , or to the enzyme-cleavable group;
R 51 , R 53 and R 54 are each, independently, a bond or optionally-substituted C 1 -C 6 alkylene;
R 52 is a bond, C 1 -C 6 alkylene, —C(O)— or —O—C(O)—;
each X 1 is independently —NR N —C(O)— or —C(O)—NR N —;
each R N independently represent H, C 1 -C 6 alkyl, or polyhydroxyl group;
R 44 and R 45 are each, independently, H, polyhydroxyl group, substituted polyhydroxyl group, —C(O)-polyhydroxyl group, or substituted —C(O)-polyhydroxyl group, wherein optional substituents are selected from sulfate, phosphate, alkyl sulfate, and alkyl phosphate, provided that R 44 and R 45 are not both H; and
each n43 is independently 2 to 26.
46 . The Linker compound of claim 45 , comprising a Polar group having one of the following structures prior to attachment to the enzyme-cleavable group and/or to the Linker Unit:
wherein:
(*) indicates the attachment site to site R b , or to the enzyme-cleavable group;
each R is independently H, alkyl or polyhydroxyl group;
R 44 and R 45 are each, independently, H, polyhydroxyl group, substituted polyhydroxyl group, —C(O)-polyhydroxyl group, or substituted —C(O)-polyhydroxyl group, wherein optional substituents are selected from sulfate, phosphate, alkyl sulfate, and alkyl phosphate, provided that R 44 and R 45 are not both H; and
each n is independently 1 to 12.
47 . The Linker compound of any one of claims 1-6 , comprising a Polar group having a formula selected from:
or a stereoisomer or salt thereof, wherein:
each Y is independently R 76 or
each R 76 is independently H, acetyl, —P(═O)(OH) 2 , or —(CH 2 ) v —O—S(═O) 2 (OH);
each R a and R b is independently H or R a and R b are taken together with the carbon to which they are attached to form an oxo group;
each q is independently 2-26;
each m is independently 1 to 4;
each n is independently 1 to 4;
each v is independently 1 to 6; and
each * is an attachment site to R b , or to the enzyme-cleavable group.
48 . The Linker compound of any one of claims 1-6 , comprising a Polar group having a formula selected from:
or a stereoisomer or salt thereof, wherein:
each R 76 is independently H, acetyl, —P(═O)(OH) 2 , or —(CH 2 ) v S(═O) 2 (OH); P
each q is independently 2-26;
each m is independently 1 to 4;
each n is independently 1 to 4;
each v is independently 1 to 6; and
each * is an attachment site to R b , or to the enzyme-cleavable group.
49 . The Linker compound of any one of claims 1-6 , comprising a Polar group having a formula selected from:
or a stereoisomer or salt thereof, wherein:
each q is independently 2-26;
each m is independently 1 to 4;
each n is independently 1 to 4; and
each * is an attachment site to R b , or to the enzyme-cleavable group.
50 . The Linker compound of claim 47 , wherein Y is R 76 .
51 . The Linker compound of claim 47 , wherein Y is
52 . The Linker compound of claim 47 , wherein each R a and R b is independently H.
53 . The Linker compound of claim 47 , wherein R a and R b are taken together with the carbon to which they are attached to form an oxo group.
54 . The Linker compound of any one of claims 45-47 , wherein q is 10-20.
55 . The Linker compound of any one of claims 57 - 49 , wherein q is 12.
56 . The Linker compound of any one of claims 1-6, 35-37, or 47-49 , comprising a Polar group selected from the following, or a stereoisomer or salt thereof:
wherein each Z is attached at * and is individually selected from:
wherein each is an attachment site to R b , or to the enzyme-cleavable group.
57 . The Linker compound of any one of claims 1 to 6 , wherein the Polar group comprises at least one Carboxyl unit having the following formula:
or a stereoisomer or salt thereof, wherein:
(a)
L 70 is selected from C 1 -C 8 alkylene, C 1 -C 8 alkylene-C(O)—, —C(O)—C 1 -C 8 alkylene-, and —C(O)—C 1 -C 8 alkylene-C(O)—, and * is an attachment site to R b , to the enzyme-cleavable group, or to a remainder of the Polar group;
R 70 is ˜NR 71 (R 72 -R 73 ), wherein R 71 is selected from H, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, or polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), R 72 is a bond or is selected from optionally substituted C 1 -C 3 alkylene, optionally substituted ether, optionally substituted thioether, optionally substituted ketone, optionally substituted amide, polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), optionally substituted carbocycle, optionally substituted aryl or optionally substituted heteroaryl, and R 73 is a carboxyl or polycarboxyl, wherein polycarboxyl comprises 1 to 10, or 1 to 6, or 1 to 4 carboxyl groups, wherein the carboxyl groups are interconnected by alkyl, alkylene, substituted alkyl, substituted alkylene, heteroalkyl, heteroalkylene, amino and/or amide; or
(b)
L 70 is selected from C 1 -C 8 alkylene, C 1 -C 8 alkylene-C(O)—, —C(O)—C 1 -C 8 alkylene-, and —C(O)—C 1 -C 8 alkylene-C(O)—, and * is an attachment site to R b , to the enzyme-cleavable group, or to a remainder of the Polar group;
R 70 is ˜NR 71 (R 75 —(R 73 ) 2 ), wherein R 71 is selected from H, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, or polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), R 75 is a branched optionally substituted C 1 -C 3 alkylene, optionally substituted ether, optionally substituted thioether, optionally substituted ketone, optionally substituted amide, polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), optionally substituted carbocycle, optionally substituted aryl or optionally substituted heteroaryl and each R 73 is independently carboxyl or polycarboxyl, wherein polycarboxyl comprises 1 to 10, or 1 to 6, or 1 to 4 carboxyl groups, wherein the carboxyl groups are interconnected by alkyl, alkylene, substituted alkyl, substituted alkylene, heteroalkyl, heteroalkylene, amino and/or amide; or
(c)
L 70 is selected from C 1 -C 8 alkylene, C 1 —C alkylene-C(O)—, —C(O)—C 1 —C alkylene-, and —C(O)—C 1 -C 8 alkylene-C(O)—, and * is an attachment site to R b , to the enzyme-cleavable group, or to a remainder of the Polar group;
R 70 is —N(R 74 -R 73 )(R 72 -R 73 ), wherein R 72 and R 74 are each independently selected from optionally substituted C 1 -C 3 alkylene, optionally substituted ether, optionally substituted thioether, optionally substituted ketone, optionally substituted amide, polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), optionally substituted carbocycle, optionally substituted aryl or optionally substituted heteroaryl, and each R 73 is independently carboxyl or polycarboxyl, wherein the polycarboxyl comprises 1 to 10, or 1 to 6, or 1 to 4 carboxyl groups, wherein the carboxyl groups are interconnected by alkyl, alkylene, substituted alkyl, substituted alkylene, heteroalkyl, heteroalkylene, amino and/or amide.
58 . The Linker compound of any one of claims 1 to 57 , comprising a Polar group including the Polymer unit and a Sugar unit.
59 . The Linker compound of any o one f claims 1 to 57 , comprising a Polar group including at least two Polymer units.
60 . The Linker compound of any one of claims 1 to 57 , comprising a Polar group including the Polymer unit and a Carboxyl unit.
61 . The Linker compound of any one of claims 1 to 57 , comprising at least two Polar groups.
62 . The Linker compound of any one of claims 1 to 57 , comprising a Polar group including the Polymer unit, the Sugar unit and the Carboxyl unit.
63 . The Linker compound of any one of claims 1 to 57 , comprising a Polar group including at least two Polymer units, at least one Sugar unit and at least one Carboxyl unit.
64 . The Linker compound of any one of claims 1 to 57 , wherein the enzyme-cleavable group comprises at least two amino acid units.
65 . The Linker compound of any one of claims 1 to 64 , comprising at least one of the Polar group attached to the enzyme-cleavable group.
66 . The Linker compound of any one of claims 1-64 , having one of the following structures:
wherein
R c is a bond or C 1-6 alkylene;
the wavy line on the amino group indicates an attachment site for a Stretcher group or, prior to attachment to the Stretcher group, indicates H;
β—is the attachment site to the at least one Polar group; and
the benzylic H on the benzylic OH is optionally replaced with a bond to at least one of the Drug units or to the linking group attached to at least one of the Drug units.
67 . The Linker compound of any one of claims 1-66 , wherein the enzyme-cleavable group comprises a peptide that is cleavable by an intracellular protease.
68 . The Linker compound of claim 67 , wherein the intracellular protease is Cathepsin B.
69 . The Linker compound of claim 68 , wherein the enzyme-cleavable group comprises a cleavable peptide including a valine-citrulline peptide, a valine-alanine peptide, a valine-lysine peptide, a phenylalanine-lysine peptide, or a glycine-glycine-phenylalanine-glycine peptide.
70 . The Linker compound of any one of claims 67-69 , comprising one of the following structures:
wherein
R c is a bond or C 1-6 alkylene;
the wavy line on the amino group indicates an attachment site for the Stretcher group; or, prior to attachment to the Stretcher group, indicates H;
β—is the attachment site to the at least one Polar group; and
the H on the benzylic OH is optionally replaced with a bond to at least one of the Drug units or to the attachment site to at least one of the Drug units.
71 . The Linker compound of any one of claims 1-5 , having one of the following structures:
wherein the wavy line on the amino group indicates an attachment site to the Stretcher group; or, prior to attachment to the Stretcher group, indicates H; and the H on the benzylic OH is optionally replaced with a bond to at least one of the Drug units or a linking group attached to the at least one of the Drug units.
72 . The Linker compound of any one of claims 1 to 69 , wherein the enzyme-cleavable group is joined to the Stretcher group by a non-peptidic linking group.
73 . The Linker compound of claim 72 , wherein the non-peptidic linking group is selected from optionally-substituted C 1 -C 10 alkylene, optionally-substituted C 2 -C 10 alkenylene, optionally-substituted C 2 -C 10 alkynylene, or optionally-substituted polyethylene glycol.
74 . The Linker compound of any one of claims 1-73 , comprising the Stretcher group attached to the enzyme-cleavable group.
75 . The Linker compound of claim 74 , wherein the Stretcher group is selected from the following:
wherein R 17 is —C 1 -C 10 alkylene-, —C 1 -C 10 heteroalkylene-, —C 3 -C 8 carbocyclo-, —O—(C 1 -C 8 alkylene)-, —(CH 2 —O—CH 2 ) b —C 1 -C 8 alkylene- (where b is 1 to 26), —C 1 -C 8 alkylene-(CH 2 —O—CH 2 ) b — (where b is 1 to 26), —C 1 -C 8 alkylene-(CH 2 —O—CH 2 ) b —C 1 -C 8 alkylene- (where b is 1 to 26), -arylene-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 1 (alkylene-(C 3 -C 8 heterocyclo)-, —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-C(═O)—, —C 1 -C 10 alkylene-C(O)NH—C 1 -C 8 alkylene-[O—CH 2 —CH 2 ] n —C(O)— (where n is 1 to 26), C 1 -C 10 heteroalkylene-C(═O)—, —C 1 -C 3 alkylene-(CH 2 —O—CH 2 ) b —C(═O)— (where b is 1 to 26), —(CH 2 —O—CH 2 ) b —C 1 -C 8 alkylene-C(═O)— (where b is 1 to 26), —C 1 -C 8 alkylene-(CH 2 —O—CH 2 ) b —C 1 -C 8 alkylene-C(═O)— (where b is 1 to 26), —C 3 -C 8 carbocyclo-C(═O)—, —O—(C 1 -C 8 alkyl)-C(═O)—, -arylene-C(═O)—, —C 1 -C 10 alkylene-arylene-C(═O)—, -arylene-C 1 -C 10 alkylene-C(═O)—, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-C(═O)—, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-C(═O)—, —C 3 -C 8 heterocyclo-C(═O)—, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-C(═O)—, —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-C(═O)—, —C 1 -C 10 alkylene-NH—, —C 1 -C 10 heteroalkylene-NH—, —C 1 -C 8 alkylene-(CH 2 —O—CH 2 ) b —NH— (where b is 1 to 26), —(CH 2 —O—CH 2 ) b —C 1 -C 8 alkylene-NH— (where b is 1 to 26), —C 1 -C 8 alkylene-(CH 2 —O—CH 2 ) b —C 1 -C 8 alkylene-NH— (where b is 1 to 26), —C 1 -C 8 alkylene-(C(═O))—NH—(CH 2 —O—CH 2 ) b —C(═O)-(where b is 1 to 26), —C 1 -C 8 alkylene-(C(═O))—NH—(CH 2 —O—CH 2 ) b —C 1 -C 8 alkylene-C(═O)-(where b is 1 to 26), —C 1 —C alkylene-NH—(C(═O))—(CH 2 —O—CH 2 ) b —NH— (where b is 1 to 26), —C 1 -C 8 alkylene-NH—(C(═O))—(CH 2 —O—CH 2 ) b —C 1 -C 8 alkylene-NH— (where b is 1 to 26), —C 3 -C 8 carbocyclo-NH—, —O—(C 1 -C 8 alkyl)-NH—, -arylene-NH—, —C 1 -C 10 alkylene-arylene-NH—, -arylene-C 1 -C 10 alkylene-NH—, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-NH—, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-NH—, —C 3 -C 8 heterocyclo-NH—, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-NH—, —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-NH—, —C 1 -C 10 alkylene-S—, C 1 -C 10 heteroalkylene-S—, —C 3 -C 8 carbocyclo-S—, —O—(C 1 -C 5 alkyl)-S—, -arylene-S—, —C 1 -C 1 (alkylene-arylene-S—, -arylene-C 1 -C 10 alkylene-S—, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-S—, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-S—, —C 3 -C 8 heterocyclo-S—, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-S—, or —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-S—; or
wherein the Stretcher group comprises maleimido(C 1 -C 10 alkylene-C(O)—, maleimido(CH 2 OCH 2 )p 2 (C 1 -C 10 alkyene)C(O)—, maleimido(C 1 -C 10 alkyene) (CH 2 OCH 2 ) p2 C(O)—, or a ring open form thereof, wherein p2 is from 1 to 26;
and wherein * is an attachment site to the Targeting group, and the wavy line is an attachment site to the enzyme-cleavable group.
76 . The Linker compound of claim 74 , wherein the Stretcher group is selected from the following:
wherein the wavy line indicates an attachment site of the Stretcher group to the enzyme-cleavable group, and the attachment site to the Targeting group is on the maleimide, primary amine or alkyne functional group.
77 . The Linker compound of claim 1 , having one of the following structures:
wherein the H on the benzylic OH is optionally replaced with a bond to the at least one Drug unit or to the linking group attached to the at least one Drug unit.
78 . A Drug-Linker compound, comprising a Linker compound of any one of the claims 1-77 attached to the at least one Drug unit, or attached to the linking group attached to the at least one Drug unit, at the attachment site.
79 . The Drug-Linker of claim 78 , wherein the Drug unit is selected from a cytotoxic agent, an immune modulatory agent, a nucleic acid, a growth inhibitory agent, a PROTAC, a toxin, a radioactive isotope, and a chelating ligand.
80 . The Drug-Linker of claim 79 , wherein the Drug unit is a cytotoxic agent.
81 . The Drug-Linker of claim 80 , wherein the cytotoxic agent is selected from the group consisting of an auristatin, a maytansinoid, a camptothecin, a duocarmycin, and a calicheamicin.
82 . The Drug-Linker of claim 81 , wherein the cytotoxic agent is an auristatin.
83 . The Drug-Linker of claim 82 , wherein the cytotoxic agent is MMAE or MMAF.
84 . The Drug-Linker of claim 81 , wherein the cytotoxic agent is a camptothecin.
85 . The Drug-Linker of claim 84 , wherein the cytotoxic agent is exatecan, or SN-38, or DxD.
86 . The Drug-Linker of claim 85 , wherein the cytotoxic agent is RS-exatecan or SS-exatecan.
87 . The Drug-Linker of claim 81 , wherein the cytotoxic agent is a calicheamicin.
88 . The Drug-Linker of claim 81 , wherein the cytotoxic agent is a maytansinoid.
89 . The Drug-Linker of claim 88 , wherein the maytansinoid is maytansine, maytansinol, or ansamatocin-2.
90 . The Drug-Linker of claim 79 , wherein the Drug unit is an immune modulatory agent.
91 . The Drug-Linker of claim 90 , wherein the immune modulatory agent is selected from a TRL7 agonist, a TLR8 agonist, a STING agonist, or a RIG-1 agonist.
92 . The Drug-Linker of claim 91 , wherein the immune modulatory agent is an TLR7 agonist.
93 . The Drug-Linker of claim 92 , wherein the TLR7 agonist is an imidazoquinoline, an imidazoquinoline amine, a thiazoquinoline, an aminoquinoline, an aminoquinazoline, a pyrido [3,2-d]pyrimidine-2,4-diamine, pyrimidine-2,4-diamine, 2-aminoimidazole, 1-alkyl-1H-benzimidazol-2-amine, tetrahydropyridopyrimidine, heteroarothiadiazide-2,2-dioxide, a benzonaphthyridine, a guanosine analog, an adenosine analog, a thymidine homopolymer, ssRNA, CpG-A, PolyG10, or PolyG3.
94 . The Drug-Linker of claim 91 , wherein the immune modulatory agent is a TLR8 agonist.
95 . The Drug-Linker of claim 94 , wherein the TLR8 agonist is selected from an imidazoquinoline, a thiazoloquinoline, an aminoquinoline, an aminoquinazoline, a pyrido [3,2-d]pyrimidine-2,4-diamine, pyrimidine-2,4-diamine, 2-aminoimidazole, 1-alkyl-1H-benzimidazol-2-amine, tetrahydropyridopyrimidine, or a ssRNA.
96 . The Drug-Linker of claim 91 , wherein the immune modulatory agent is a STING agonist.
97 . The Drug-Linker of claim 91 , wherein the immune modulatory agent is a RIG-1 agonist.
98 . The Drug-Linker of claim 97 , wherein the RIG-1 agonist is selected from KIN1148, SB-9200, KIN700, KIN600, KIN500, KIN100, KIN101, KIN400, and KIN2000.
99 . The Drug-Linker of claim 79 , wherein the Drug unit is a chelating ligand.
100 . The Drug-Linker of claim 99 , wherein the chelating ligand is selected from platinum (Pt), ruthenium (Ru), rhodium (Rh), gold (Au), silver (Ag), copper (Cu), molybdenum (Mo), titanium (Ti), or iridium (Ir); a radioisotope such as yittrium-88, yittrium-90, technetium-99, copper-67, rhenium-188, rhenium-186, galium-66, galium-67, indium-111, indium-114, indium-115, lutetium-177, strontium-89, sararium-153, and lead-212.
101 . The Drug-Linker of claim 78 , having one of the following structures:
102 . A conjugate comprising a Targeting group attached to the Drug-linker of any one of claims 78 to 101 , wherein the Targeting group specifically binds to the target molecule.
103 . The conjugate of claim 102 , wherein the Targeting group is selected from an antibody or an antigen-binding portion thereof.
104 . The conjugate of claim 103 , wherein the Targeting group is a monoclonal antibody, a Fab, a Fab′, an F(ab′), an Fv, a disulfide linked Fc, a scFv, a single domain antibody, a diabody, a bi-specific antibody, or a multi-specific antibody.
105 . The conjugate of claim 102 , wherein the Targeting group is a diabody, a DART, an anticalin, an affibody, an avimer, a DARPin, or an adnectin.
106 . The conjugate of any one of claims 102 to 105 , wherein the Targeting group is mono-specific.
107 . The conjugate of any one of claims 102 to 106 , wherein the Targeting group is bivalent.
108 . The conjugate of any one of claims 102 to 105 , wherein the Targeting group is bispecific.
109 . The conjugate of any one of claims 102 to 108 , wherein the average drug loading (p load ) of the conjugate is from about 1 to about 8, about 2, about 4, about 6, about 8, about 10, about 12, about 14, about 16, about 3 to about 5, about 6 to about 8, or about 8 to about 16.
110 . The conjugate of any one of claims 107-109 , selected from the following:
wherein Ab is a Targeting group and n is p load .
111 . The conjugate of any one of claims 102-110 , wherein the target molecule is CD19, CD20, CD30, CD33, CD70, LIV-1, EGFRv3, or HER2.
112 . The conjugate of any one of claims 102-111 , wherein the target molecule is a cancer associated antigen.
113 . The conjugate of any one of claims 102-111 , wherein the target molecule is CD19, CD20, CD30, CD33, CD38, CA125, HER2, MUC-1, prostate-specific membrane antigen (PSMA), CD44 surface adhesion molecule, mesothelin (MLSN), carcinoembryonic antigen (CEA), epidermal growth factor receptor (EGFR), EGFRvIII, vascular endothelial growth factor receptor-2 (VEGFR2), high molecular weight-melanoma associated antigen (HMW-MAA), MAGE-A1, IL-13R-a2, GD2, 1p19q, HER2, ABL1, AKT1, ALK, APC, AR, ATM, BRAF, BRCA1, BRCA2, cKIT, cMET, CSF1R, CTNNB1, FGFR1, FGFR2, FLT3, GNA11, GNAQ, GNAS, HRAS, IDH1, IDH2, JAK2, KDR (VEGFR2), KRAS, MGMT, MGMT-Me, MLH1, MPL, NOTCHI, NRAS, PDGFRA, Pgp, PIK3CA, PR, PTEN, RET, RRM1, SMO, SPARC, TLE3, TOP2A, TOPO1, TP53, TS, TUBB3, VHL, CDH1, ERBB4, FBXW7, HNF1A, JAK3, NPM1, PTPN11, RB1, SMAD4, SMARCB1, STK1, MLH1, MSH2, MSH6, PMS2, ROS1, ERCC1, 5T4 (TPBG), B7-H3, CCR7, CD105, CD22, CD46, CD47, CD56, CD70, CD71, CD79b, CDH6, CLDN6, CLDN18.2, CLEC12A, DLL3, DR5, ERBB3 (HER3), EPCAM, FOLR1, IGF1R, IL2RA (CD25), IL3RA, ITGB6, LIV-1, LRRC15, mesothelin (MSLN), NaPi2b (SLC34A2), nectin-4, PTK7, ROR1, SEZ6, SLC44A4, SLITRK6, Tissue Factor (TF), TROP2, or B7-H4.
114 . The conjugate of any one of claims 102-104 , wherein the Targeting group is an antibody, or fragment thereof, comprising rituximab (Rituxan®), trastuzumab (Herceptin®), pertuzumab (Perjeta®)), bevacizumab (Avastin®), ranibizumab (Lucentis®), cetuximab (Erbitux®), alemtuzumab (Campath®), panitumumab (Vectibix®), ibritumomab tiuxetan (Zevalin®), tositumomab (Bexxar®), ipilimumab, zalutumumab, dalotuzumab, figitumumab, ramucirumab, galiximab, farletuzumab, ocrelizumab, ofatumumab (Arzerra®), tositumumab, ibritumomab, the CD20 antibodies 2F2 (HuMax-CD20), 7D8, IgM2C6, IgG1 2C6, 11B8, B1, 2H7, LT20, 1FS or AT80, daclizumab (Zenapax®), or anti-LHRH receptor antibodies including clone A9E4, F1G4, AT2G7, GNRH03, or GNRHR2.
115 . A pharmaceutical composition comprising the conjugate of any one of claims 102 to 114 and a pharmaceutically acceptable carrier.
116 . A method of treating a subject in need thereof, comprising administering to the subject a conjugate of any one of claims 102 to 114 or the pharmaceutical composition of claim 115 , wherein the subject has cancer or an autoimmune disease and the conjugate binds to the target antigen associated with the cancer or autoimmune disease.
117 . A Drug-Linker compound, represented by the structure of Formula (A)
or a salt thereof, wherein:
(i) β is R 20 (—R 21 —[O—CH 2 —CH 2 ] n20 —R 22 —NR 24 R 25 )z; wherein
R 20 is NH, H,
R 21 and R 22 are each, independently, a bond or C 1 -C 3 alkylene;
R 24 and R 25 are each independently selected from H; polyhydroxyl group; and —C(O)— polyhydroxyl group; provided that R 24 and R 25 are not both H; z is 1, or 2; and
n20 is 2 to 26;
(ii) R a is H or C 1 -C 6 alkyl;
(iii) R c is a bond, —C(O)—, —S(O)—, —SO 2 —, C 1-6 alkylene, C 1-6 alkynylene, or C 1-6 alkynylene-triazolyl;
(iv) R 1 is a bond, —C(O)—, or C 1-6 alkylene; and
(v) δ is selected from a Drug;
(vi) α is represented by
wherein
R 2 is a peptide having 2-5 amino acids;
R 3 is —C 1 -C 10 alkylene-C(═O)—, —C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-C(O)NH—C 1 -C 8 alkylene-[O—CH 2 —CH 2 ] n —C(O)— (where n is 1 to 26), or —C 1 -C 8 alkylene-(CH 2 —O—CH 2 ) b —C(═O)— (where b is 1 to 26).
118 . The Drug-Linker compound of claim 117 , wherein R 20 is
119 . The Drug-Linker compound of claim 117 , wherein β is
and n20 is 4 to 12.
120 . The Drug-Linker compound of claim 117 , wherein β is
121 . The Drug-Linker compound of any one of claims 117 to 120 , wherein R 2 is selected from:
122 . The Drug-Linker compound of any one of claims 117 to 121 , wherein R 2 is selected from:
123 . The Drug-Linker compound of any one of claims 117 to 122 , wherein R 3 is selected from:
124 . The Drug-Linker compound of any one of claims 117 to 123 , wherein R 3 is selected from:
125 . The Drug-Linker compound of any one of claims 117 to 124 , wherein R c is —C(O)—.
126 . The Drug-Linker compound of any one of claims 117 to 125 , wherein R 1 is —C(O)—.
127 . The Drug-Linker compound of any one of claims 117 to 126 , wherein the Drug is selected from a cytotoxic agent.
128 . The Drug-Linker compound of any one of claims 117 to 126 , wherein the Drug is MMAE or MMAF.
129 . The Drug-Linker compound of any one of claims 117 to 126 , wherein the Drug is MMAE.
130 . The Drug-Linker compound of any one of claims 117 to 126 , wherein the Drug is exatecan.
131 . The Drug-Linker compound of any one of claims 117 to 126 , wherein the Drug is selected from an immune modulatory agent.
132 . The Drug-Linker compound of any one of claims 117 to 126 , wherein δ is selected from
133 . The Drug-Linker compound of any one of claims 117 to 126 , wherein δ is
134 . The Drug-Linker compound of any one of claims 117 to 126 , wherein δ is from
135 . A conjugate comprising a Targeting group attached to the Drug-linker of any one of claims 117 to 134 , wherein the Targeting group specifically binds to the target molecule.
136 . The conjugate of claim 135 , wherein the ratio of Drug-Linker to Targeting group is represented by a DAR value, wherein the DAR value is from 1 to 8.Join the waitlist — get patent alerts
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